Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study

Sherko Kuemmel,Servando Cardona-Huerta,Flavia Morales-Vásquez,Jose Manuel Pérez-García,Jacinta Abraham,Carlo A Tondini,Alejandro Juárez-Ramiro,Mark Benyunes,Miguel Martín,Erika Hitre,Bartosz Itrych,Zbigniew Nowecki,Marco Sequi,Eleonora Restuccia,Estefania Monturus,Bogusława Karaszewska

doi:10.1007/s10549-021-06145-3

Abstract

PurposeIntravenous trastuzumab, pertuzumab, and docetaxel are first-line standard of care for patients with HER2-positive metastatic breast cancer (mBC). MetaPHER is the first study assessing the safety and tolerability of subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy in a global patient population with HER2-positive mBC.MethodsIn this open-label, single-arm, multicenter, phase 3b study, eligible patients were ≥ 18 years old with histologically/cytologically confirmed previously untreated HER2-positive mBC. All received ≥ 1 subcutaneous trastuzumab 600 mg fixed dose plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance: 420 mg/kg) and docetaxel (≥ 6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy.ResultsAt clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia; the most common grade ≥ 3 events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%.ConclusionsSafety and efficacy with subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in mBC are consistent with historical evidence of intravenous trastuzumab with this combination. Findings further support subcutaneous administration not affecting safety/efficacy profiles of trastuzumab in HER2-positive BC with increased flexibility in patient care. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection has recently been approved for the treatment of HER2-positive early/mBC, further addressing the increasing relevance of and need for patient-centric treatment strategies.Trial registrationNCT02402712

Highlights

In previously untreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, the pivotal phase 3 CLEOPATRA study demonstrated improved progression-free survival (PFS: 18.5 vs. 12.4 months, hazard ratio [HR] 0.62; 95% confidence interval, 0.51–0.75; P < 0.001), as assessed by an independent review facility, with first-line intravenous fixed-dose pertuzumab (P IV), weight-based intravenous trastuzumab (H IV), and docetaxel (D IV) compared with placebo, H IV, and D IV
Phase 2 and 3 studies have reported higher patient preference and healthcare professional satisfaction with Subcutaneous trastuzumab (H SC) compared with H IV, in both HER2positive early breast cancer and metastatic breast cancer (mBC) (PrefHer and MetaspHer, respectively) [11,12,13]
As MetaPHER was a single-arm study, no comparator arm is available for direct comparisons of H SC plus P IV and D IV with H IV plus P IV and D IV

Summary

Introduction

In previously untreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC), the pivotal phase 3 CLEOPATRA study demonstrated improved progression-free survival (PFS: 18.5 vs. 12.4 months, hazard ratio [HR] 0.62; 95% confidence interval, 0.51–0.75; P < 0.001), as assessed by an independent review facility, with first-line intravenous fixed-dose pertuzumab (P IV), weight-based intravenous trastuzumab (H IV), and docetaxel (D IV) compared with placebo, H IV, and D IV. Subcutaneous trastuzumab (H SC) contains a fixed dose of 600 mg of H co-formulated with 2000 U/m of recombinant human hyaluronidase (rHuPH20), a permeant enhancer that allows absorption and dispersion of large fluid volumes through degradation of hyaluronan [9]. It can be administered in ~ 2–5 min and has been shown to reduce patient chair and active healthcare professional time, compared with H IV (20.9 vs 77.8 min [P < 0.0001] and 5.1 vs 20.8 min [P < 0.0001], respectively) [8, 10]. Phase 2 and 3 studies have reported higher patient preference and healthcare professional satisfaction with H SC compared with H IV, in both HER2positive early breast cancer (eBC) and mBC (PrefHer and MetaspHer, respectively) [11,12,13]

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